Conjugated bilirubin in neonates with glucose-6-phosphate dehydrogenase deficiency

doi:10.1016/S0022-3476(96)80138-7

The Journal of Pediatrics

Volume 128, Issue 5, May 1996, Pages 695-697

https://doi.org/10.1016/S0022-3476(96)80138-7 Get rights and content

We used a system capable of measuring conjugated bilirubin and its monoconjugated and diconjugated fractions in serum to assess bilirubin conjugation in 29 glucose-6-phosphate dehydrogenase (G6PD) -deficient, term, male newborn infants and 35 control subjects; all had serum bilirubin levels≥256 μmol/L (15 mg/ dl). The median value for diconjugated bilirubin was lower in the G6PD-deficient neonates than in control subjects (0.06 (range 0.00 to 1.84) vs 0.21 (range 0.00 to 1.02) μmol/L, p = 0.006). Diglucuronide was undetectable in 11 (38.9%) of the G6PD-deficient infants versus 3 (8.6%) of the control subjects (p = 0.015). These findings imply a partial defect of bilirubin conjugation not previously demonstrated in G6PD-deficient newborn infants.

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Although all cases in our current study were safely managed in our well-resourced facility, our findings suggest that both historically and in less well-resourced facilities or in the community today, G6PD c.202 deficiency could be a significant cause of long-term neurological damage due to neonatal hyperbilirubinemia.28 Our data support the conclusion made by others29 that G6PD c.202 deficiency does not cause neonatal jaundice through a mechanism that predominantly involves hemolysis. Although mean Hb concentrations were significantly lower in homo/hemizygous-deficient than in wild-type homo/hemizygous wild-type neonates, the difference was small (138 g/L vs 146 g/L) and the prevalence of neither anemia nor severe anemia was significantly increased.
Few previous studies have reported the effects of glucose-6-phosphate dehydrogenase (G6PD)–deficiency on child health in Africa. We conducted a case-control study in which cases (n = 6829) were children admitted, for any reason, to Kilifi County Hospital, Kenya, while controls (n = 10 179) were recruited from the surrounding community. Cases were subclassified based on their clinical and laboratory findings at admission. We calculated the prevalence of specific diseases by G6PD c.202 genotype, the only significant cause of G6PD-deficiency in this area, then estimated the association between genotype and admission with specific conditions using logistic regression. Among neonates, the prevalence of jaundice was higher in both G6PD c.202T heterozygotes (40/88; 45.5%; P = .004) and homo/hemizygotes (81/134; 60.5%; P < .0001) than in wild-type homozygotes (157/526; 29.9%). Median bilirubin levels also increased across the groups, being highest (239 mmol/L; interquartile range 96-390 mmol/L) in G6PD c.202T homo/hemizygotes. No differences were seen in admission hemoglobin concentrations or the prevalence of anemia or severe anemia by G6PD c.202 genotype. On case control analysis, G6PD heterozygosity was negatively associated with all-cause hospital admission (odds ratio 0.81; 95% confidence interval 0.73-0.90; P < .0001) and, specifically, admission with either pneumonia or Plasmodium falciparum parasitemia; while, conversely, it was positively associated with Gram-positive bacteremia. G6PD c.202T homo/heterozygosity was positively associated with neonatal jaundice, severe pneumonia, the receipt of a transfusion, and in-patient death. Our study supports the conclusion that G6PD c.202T is a balanced polymorphism in which a selective advantage afforded to heterozygous females against malaria is counterbalanced by increased risks of neonatal jaundice, invasive bacterial infections, and anemia.
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The Preterm Infant. A High-Risk Situation for Neonatal Hyperbilirubinemia Due to Glucose-6-Phosphate Dehydrogenase Deficiency
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G6PD-deficient neonates frequently develop a more moderate form of hyperbilirubinemia, in the main responsive to phototherapy, but sometimes requiring exchange transfusion. The pathophysiology of this hyperbilirubinemia includes a combination of increased hemolysis12 and a predilection for diminished bilirubin conjugation,13 the result, at least in part, of an interaction with a (TA)7 promoter polymorphism of the uridine diphosphate (UDP)-glucuronosyltransferase 1A1 gene (UGT1A1*28) associated with Gilbert syndrome.14 Premature infants are at higher risk for neonatal hyperbilirubinemia and its consequent neurotoxic complications than that for term infants.
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In addition, infections also have been implicated in the pathogenesis of this acute hemolysis [29]. Having an impaired ability to conjugate (and hence eliminate) bilirubin also contributes to the development of hyperbilirubinemia [31]. The hepatic enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) is responsible for conjugating bilirubin to mono- and diglucuronides prior to excretion into the bile.
The pathologic phenotype of severe hyperbilirubinemia in the newborn infant is primarily due to excessive bilirubin production and/or impaired conjugation, resulting in an increased bilirubin load. This may, in turn, increase an infant's risk for the development of bilirubin-induced neurologic dysfunction (BIND). The highest-risk infants are those with increased bilirubin production rates due to hemolysis. Several immune and non-immune conditions have been found to cause severe hemolysis, and these are often exacerbated in those infants with perinatal sepsis and genetic predispositions. Therefore, identification of these infants, with novel technologies, is paramount in reducing the incidence of BIND and the long-term neurologic sequelae for these at-risk infants.
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Citation Excerpt :
The principle behind this methodology is that small quantities of conjugated bilirubin fractions efflux from the hepatocyte to the serum, and serum determinations of these fractions reflect intrahepatocytic conjugated bilirubin, reflective of bilirubin conjugation.41 Lower serum diconjugated bilirubin fractions were demonstrated in hyperbilirubinemic (STB ≥ 256 μmol/L [15 mg/dL]) G6PD-deficient neonates, compared with G6PD-adequate controls with similar STB values.42 Furthermore, diminished serum total and conjugated bilirubin fractions were found in G6PD-deficient neonates who subsequently developed hyperbilirubinemia compared with those in whom STB remained <256 μmol/L (15 mg/dL).43
Glucose-6-phosphate dehydrogenase deficiency is a commonly occurring genetic condition, likely to be encountered today in virtually any corner of the globe. Sudden episodes of hemolysis associated with the condition may result in exponential increases in serum total bilirubin concentrations to levels at which bilirubin-induced neurologic damage may occur. The hyperbilirubinemia is the result of complex interactions between genes and environment. Neonatal screening programs coupled with parental and medical caretaker education may be successful in limiting the severity of disease.

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: Supported in part by the General Research Fund of the Shaare Zedek Medical Center.

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Conjugated bilirubin in neonates with glucose-6-phosphate dehydrogenase deficiency

J Pediatr

Blood

Gastroenterology

J Pediatr

Neonatal hyperbilirubinemia associated with glucose-6-phosphate dehydrogenase deficiency in Sephardic-Jewish infants: incidence, severity and the effect of phototherapy

Pediatrics

Hidden risks: early discharge and bilirubin toxicity due to glucose 6-phosphate dehydrogenase deficiency

Pediatrics

Liquid-chromatographic assay and identification of mono- and diester conjugates of bilirubin in normal serum

Clin Chem